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International Journal of Molecular... Sep 2023Primary and secondary non-response affects approximately 50% of patients with Crohn's disease treated with anti-tumour necrosis factor (TNF) monoclonal antibodies. To...
Primary and secondary non-response affects approximately 50% of patients with Crohn's disease treated with anti-tumour necrosis factor (TNF) monoclonal antibodies. To date, very little single cell research exists regarding drug repurposing in Crohn's disease. We aimed to elucidate the cellular phenomena underlying resistance to anti-TNF therapy in patients with Crohn's disease and to identify potential drug candidates for these patients. Single-cell transcriptome analyses were performed using data (GSE134809) from the Gene Expression Omnibus and Library of Integrated Network-Based Cellular Signatures L1000 Project. Data aligned to the Genome Reference Consortium Human Build 38 reference genome using the Cell Ranger software were processed using the Seurat package. To capture significant functional terms, gene ontology functional enrichment analysis was performed on the marker genes. For biological analysis, 93,893 cells were retained (median 20,163 genes). Through marker genes, seven major cell lineages were identified: B-cells, T-cells, natural killer cells, monocytes, endothelial cells, epithelial cells, and tissue stem cells. In the anti-TNF-resistant samples, the top 10 differentially expressed genes were , , , , , , , , , , , , and , which were robustly distributed in all cell lineages, mainly in B-cells. Through molecular function analyses, we found that the biological functions of both monocyte and T-cell groups mainly involved immune-mediated functions. According to multi-cluster drug repurposing prediction, vorinostat is the top drug candidate for patients with anti-TNF-refractory Crohn's disease. Differences in cell populations and immune-related activity within tissues may influence the responsiveness of Crohn's disease to anti-TNF agents. Vorinostat may serve as a promising novel therapy for anti-TNF-resistant Crohn's disease.
PubMed: 37762402
DOI: 10.3390/ijms241814099 -
Biomolecules Aug 2023Neuroplasticity is a crucial property of the central nervous system to change its activity in response to intrinsic or extrinsic stimuli. This is mainly achieved through... (Review)
Review
Neuroplasticity is a crucial property of the central nervous system to change its activity in response to intrinsic or extrinsic stimuli. This is mainly achieved through the promotion of changes in the epigenome. One of the epi-drivers priming this process is suberoylanilide hydroxamic acid (SAHA or Vorinostat), a pan-histone deacetylase inhibitor that modulates and promotes neuroplasticity in healthy and disease conditions. Knowledge of the specific molecular changes induced by this epidrug is an important area of neuro-epigenetics for the identification of new compounds to treat cognition impairment and/or epilepsy. In this review, we summarize the findings obtained in cellular and animal models of various brain disorders, highlighting the multiple mechanisms activated by SAHA, such as improvement of memory, learning and behavior, and correction of faulty neuronal functioning. Supporting this evidence, and data underline how SAHA positively regulates the expression of neuronal genes and microtubule dynamics, induces neurite outgrowth and spine density, and enhances synaptic transmission and potentiation. In particular, we outline studies regarding neurodevelopmental disorders with pharmaco-resistant seizures and/or severe cognitive impairment that to date lack effective drug treatments in which SAHA could ameliorate defective neuroplasticity.
PubMed: 37759701
DOI: 10.3390/biom13091301 -
World Journal of Gastroenterology Sep 2023Hepatocellular carcinoma (HCC) is a common clinical condition with a poor prognosis and few effective treatment options. Potent anticancer agents for treating HCC must...
BACKGROUND
Hepatocellular carcinoma (HCC) is a common clinical condition with a poor prognosis and few effective treatment options. Potent anticancer agents for treating HCC must be identified. Epigenetics plays an essential role in HCC tumorigenesis. Suberoylanilide hydroxamic acid (SAHA), the most common histone deacetylase inhibitor agent, triggers many forms of cell death in HCC. However, the underlying mechanism of action remains unclear. Family with sequence similarity 134 member B (FAM134B)-induced reticulophagy, a selective autophagic pathway, participates in the decision of cell fate and exhibits anticancer activity. This study focused on the relationship between FAM134B-induced reticulophagy and SAHA-mediated cell death.
AIM
To elucidate potential roles and underlying molecular mechanisms of reticulophagy in SAHA-induced HCC cell death.
METHODS
The viability, apoptosis, cell cycle, migration, and invasion of SAHA-treated Huh7 and MHCC97L cells were measured. Proteins related to the reticulophagy pathway, mitochondria-endoplasmic reticulum (ER) contact sites, intrinsic mitochondrial apoptosis, and histone acetylation were quantified using western blotting. ER and lysosome colocalization, and mitochondrial Ca levels were characterized confocal microscopy. The level of cell death was evaluated through Hoechst 33342 staining and propidium iodide colocalization. Chromatin immunoprecipitation was used to verify histone H4 lysine-16 acetylation in the promoter region.
RESULTS
After SAHA treatment, the proliferation of Huh7 and MHCC97L cells was significantly inhibited, and the migration and invasion abilities were greatly blocked . This promoted apoptosis and caused G1 phase cells to increase in a concentration-dependent manner. Following treatment with SAHA, ER-phagy was activated, thereby triggering autophagy-mediated cell death of HCC cells . Western blotting and chromatin immunoprecipitation assays confirmed that SAHA regulated FAM134B expression by enhancing the histone H4 lysine-16 acetylation in the promoter region. Further, SAHA disturbed the Ca homeostasis and upregulated the level of autocrine motility factor receptor and proteins related to mitochondria-endoplasmic reticulum contact sites in HCC cells. Additionally, SAHA decreased the mitochondrial membrane potential levels, thereby accelerating the activation of the reticulophagy-mediated mitochondrial apoptosis pathway and promoting HCC cell death .
CONCLUSION
SAHA stimulates FAM134B-mediated ER-phagy to synergistically enhance the mitochondrial apoptotic pathway, thereby enhancing HCC cell death.
Topics: Humans; Vorinostat; Carcinoma, Hepatocellular; Histones; Lysine; Liver Neoplasms; Cell Death; Autophagy
PubMed: 37753370
DOI: 10.3748/wjg.v29.i34.5038 -
Pharmacological Research Oct 2023Vorinostat (SAHA) is a histone deacetylase inhibitor that exerts its effects through epigenetic regulation. Specifically, SAHA can inhibit the proliferation of...
Vorinostat (SAHA) is a histone deacetylase inhibitor that exerts its effects through epigenetic regulation. Specifically, SAHA can inhibit the proliferation of triple-negative breast cancer (TNBC) cells alone or in combination with other chemotherapeutic agents. Doxorubicin (DOX), a traditional chemotherapeutic drug, exhibits a potent cytotoxic effect on cancer cells while also inducing strong toxic effects. In this study, we investigated the synergistic potential of these two drugs in combination against TNBC. Our results suggested that the combination of these two drugs could enhance the inhibitory effect on cancer cell proliferation, resulting in alterations in cell mitotic phase, and suppression of cancer cell stemness. Moreover, our in vivo study unveiled that when SAHA was combined with DOX, it not only exhibited an inhibitory effect on tumor metastasis but also played a role in regulating the immune microenvironment within tumors. Overall, the combination of DOX and SAHA presents a promising avenue for innovative combination chemotherapy in the context of TNBC.
PubMed: 37716547
DOI: 10.1016/j.phrs.2023.106926 -
Cancer Biology & Therapy Dec 2023Lung adenocarcinoma is one of the leading causes of cancer-related mortality globally. Various treatment approaches and drugs had little influence on overall survival;... (Meta-Analysis)
Meta-Analysis
Lung adenocarcinoma is one of the leading causes of cancer-related mortality globally. Various treatment approaches and drugs had little influence on overall survival; thus, new drugs and treatment strategies are needed. Drug repositioning (repurposing) seems a favorable approach considering that developing new drugs needs much more time and costs. We performed a meta-analysis on 6 microarray datasets to obtain the main genes with significantly altered expression in lung adenocarcinoma. Following that, we found major gene clusters and hub genes. We assessed their enrichment in biological pathways to get insight into the underlying biological process involved in lung adenocarcinoma pathogenesis. The L1000 database was explored for drug perturbations that might reverse the expression of differentially expressed genes in lung adenocarcinoma. We evaluated the potential drug combinations that interact the most with hub genes and hence have the most potential to reverse the disease process. A total of 2148 differentially expressed genes were identified. Six main gene clusters and 27 significant hub genes mainly involved in cell cycle regulation have been identified. By assessing the interaction between 3 drugs and hub genes and information gained from previous clinical investigations, we suggested the three possible repurposed drug combinations, Vorinostat - Dorsomorphin, PP-110 - Dorsomorphin, and Puromycin - Vorinostat with a high chance of success in clinical trials.
Topics: Humans; Drug Repositioning; Vorinostat; Adenocarcinoma of Lung; Drug Combinations; Lung Neoplasms
PubMed: 37710391
DOI: 10.1080/15384047.2023.2253586 -
Advanced Science (Weinheim,... Nov 2023One major characteristic of tumor cells is the aberrant activation of epigenetic regulatory elements, which remodel the tumor transcriptome and ultimately...
One major characteristic of tumor cells is the aberrant activation of epigenetic regulatory elements, which remodel the tumor transcriptome and ultimately promote cancer progression and drug resistance. However, the oncogenic functions and mechanisms of ovarian cancer (OC) remain elusive. Here, super-enhancer (SE) regulatory elements that are aberrantly activated in OC are identified and it is found that SEs drive the relative specific expression of the transcription factor KLF5 in OC patients and poly(ADP-ribose) polymerase inhibitor (PARPi)-resistant patients. KLF5 expression is associated with poor outcomes in OC patients and can drive tumor progression in vitro and in vivo. Mechanistically, KLF5 forms a transcriptional complex with EHF and ELF3 and binds to the promoter region of RAD51 to enhance its transcription, strengthening the homologous recombination repair (HRR) pathway. Notably, the combination of suberoylanilide hydroxamic acid (SAHA) and olaparib significantly inhibits tumor growth and metastasis of PARPi-resistant OC cells with high KLF5. In conclusion, it is discovered that SEs-driven KLF5 is a key regulatory factor in OC progression and PARPi resistance; and potential therapeutic strategies for OC patients with PARPi resistance and high KLF5 are identified.
Topics: Humans; Female; Poly(ADP-ribose) Polymerase Inhibitors; Drug Resistance, Neoplasm; Antineoplastic Agents; Ovarian Neoplasms; Vorinostat; Kruppel-Like Transcription Factors
PubMed: 37702443
DOI: 10.1002/advs.202304638 -
Journal of Comparative Effectiveness... Oct 2023Due to extensive treatment switching in the MAVORIC trial, lack of UK regulatory licence for the comparator, overall survival (OS) with mogamulizumab was compared with...
Due to extensive treatment switching in the MAVORIC trial, lack of UK regulatory licence for the comparator, overall survival (OS) with mogamulizumab was compared with patients with previously treated advanced mycosis fungoides/Sézary syndrome (MF/SS) in real-world setting. Data were from the Hospital Episode Statistics database (all patients in NHS secondary care system in 2009-2019). Patients were selected according to trial inclusion criteria, then trial and HES samples were matched on selected variables with significant imbalance. The analysis indicated significant improvement in OS for mogamulizumab treatment compared with UK clinical practice (hazard ratio: 0.36, 95% CI: 0.24, 0.53). Results suggest an OS advantage for patients with advanced MF/SS treated with mogamulizumab in MAVORIC trial compared with UK clinical practice.
Topics: Humans; Sezary Syndrome; Standard of Care; Skin Neoplasms; Mycosis Fungoides; Lymphoma, T-Cell, Cutaneous; United Kingdom
PubMed: 37642410
DOI: 10.57264/cer-2023-0017 -
Genes Jul 2023Cell proliferation and invasion are characteristic of many tumors, including ameloblastoma, and are important features to target in possible future therapeutic...
UNLABELLED
Cell proliferation and invasion are characteristic of many tumors, including ameloblastoma, and are important features to target in possible future therapeutic applications.
OBJECTIVE
The objective of this study was the identification of key genes and inhibitory drugs related to the cell proliferation and invasion of ameloblastoma using bioinformatic analysis.
METHODS
The H10KA_07_38 gene profile database was analyzed by Rstudio and ShinyGO Gene Ontology enrichment. String, Cytoscape-MCODE, and Kaplan-Meier plots were generated, which were subsequently validated by RT-qPCR relative expression and immunoexpression analyses. To propose specific inhibitory drugs, a bioinformatic search using Drug Gene Budger and DrugBank was performed.
RESULTS
A total of 204 significantly upregulated genes were identified. Gene ontology enrichment analysis identified four pathways related to cell proliferation and cell invasion. A total of 37 genes were involved in these pathways, and 11 genes showed an MCODE score of ≥0.4; however, only SLC6A3, SOX10, and LRP5 were negatively associated with overall survival (HR = 1.49 ( = 0.0072), HR = 1.55 ( = 0.0018), and HR = 1.38 ( = 0.025), respectively). The RT-qPCR results confirmed the significant differences in expression, with overexpression of >2 for SLC6A3 and SOX10. The immunoexpression analysis indicated positive LRP5 and SLC6A3 expression. The inhibitory drugs bioinformatically obtained for the above three genes were parthenolide and vorinostat.
CONCLUSIONS
We identify LRP5, SLC6A3, and SOX10 as potentially important genes related to cell proliferation and invasion in the pathogenesis of ameloblastomas, along with both parthenolide and vorinostat as inhibitory drugs that could be further investigated for the development of novel therapeutic approaches against ameloblastoma.
Topics: Humans; Ameloblastoma; Vorinostat; Cell Proliferation; Computational Biology; SOXE Transcription Factors; Low Density Lipoprotein Receptor-Related Protein-5; Dopamine Plasma Membrane Transport Proteins
PubMed: 37628576
DOI: 10.3390/genes14081524 -
BioRxiv : the Preprint Server For... Aug 2023Advanced prostate cancer (PCa) is overwhelmingly resistant to immune checkpoint blockade (ICB) therapy, representing a formidable clinical challenge. In this study, we...
Advanced prostate cancer (PCa) is overwhelmingly resistant to immune checkpoint blockade (ICB) therapy, representing a formidable clinical challenge. In this study, we developed a syngeneic murine PCa model with acquired ICB resistance. Using this model, synergistic efficacy was achieved by combining anti-PD1 and anti-CTLA4 antibodies with histone deacetylase inhibitor (HDACi) vorinostat, a cyclic ketogenic diet (CKD), or supplementation of ketone body β-hydroxybutyrate (BHB, endogenous HDACi) via 1,3-butanediol-admixed food. CKD and BHB supplementation delayed PCa tumors as monotherapy, and both BHB and adaptive immunity are required for the anti-tumor activity of CKD. Single-cell transcriptomic and proteomic profiling revealed that the HDACi and ketogenesis-enhanced ICB therapy involves cancer-cell-intrinsic (upregulated MHC class I molecules) and extrinsic mechanisms (CD8 T cell chemoattraction, M1/M2 macrophage rebalancing, monocyte differentiation toward antigen presenting cells, and diminished neutrophils). Overall, these findings underscore the potential of using HDACi and optimized KD to enhance ICB therapy for PCa.
PubMed: 37609341
DOI: 10.1101/2023.08.07.552383 -
Heliyon Aug 2023Adenoid cystic carcinoma (ACC) is a rare salivary gland cancer. The vast majority of clinical trials evaluating systemic therapy efficacy in solid tumors use the...
RATIONALE AND OBJECTIVES
Adenoid cystic carcinoma (ACC) is a rare salivary gland cancer. The vast majority of clinical trials evaluating systemic therapy efficacy in solid tumors use the Response Evaluation Criteria in Solid Tumors (RECIST) to measure response that is limited to 2 dimensional only evaluations, not taking volume or density into account. The indolent behavior ACC represents a challenge toward an appropriate evaluation of therapy response. Objectives: 1) To describe and contrast volumetric and density changes at each time-point, including changes noted from baseline to best response, to currently used 2 dimensional-only criteria (RECIST) and 2) To report the coefficient of variation in volume measurement among three reviewers on a subset of ACC patients.
MATERIALS AND METHODS
We retrospectively assessed a cohort of 18 prospectively treated patients with ACC in a phase 2 trial with vorinostat using a volumetric (viable tumor volume, VTV) and density criteria. Three independent and blinded observers segmented target lesions across a sample of randomly selected computed tomography (CT) exams to examine inter-observer variation.
RESULTS
We found that the average coefficient of variation among observers for all target lesions was 16.1%, with lung lesions displaying a smaller variation at 14.0% (p-value >0.17). We describe examples of decrease in volume and density in several lesions despite stable disease by RECIST.
CONCLUSION
This pilot study demonstrates that two-dimensional criteria such as RECIST may not be the best criteria to assess response to therapy, especially with evolving tools within picture archiving and communication system (PACS) that can assess volumetric size, density and texture, however, this should be prospectively studied.
PubMed: 37593628
DOI: 10.1016/j.heliyon.2023.e18680